This Career Development Award (K23) will provide the candidate the necessary training to establish a program of research related to understanding how key neurobehavioral risk factors (i.e., irregular central pain processing, sleep disturbance, and negative thinking) impact neurobiological mechanisms (i.e., endogenous opioid function) that contribute to individual differences in pain outcomes. Chronic pain is a major health problem affecting a significant proportion of the American population and is associated with substantial suffering and economic burden. Sleep disturbance, mood, and aberrant central pain processing have been identified as important predictors of chronic pain and disability, and have been indirectly associated with impaired endogenous opioid function. The proposed research plan will systematically address the utility of a direct pre-surgical test of endogenous opioid function via naloxone challenge in predicting pain and opioid analgesic use following total knee arthroplasty (TKA) in patients with knee osteoarthritis (OA), one of the most prevalent chronic pain conditions and predicted to drastically increase as the U.S. population ages. Specific training aims of this K23 include mentorship, didactics, and experiences designed to develop expertise in the neurobiology of pain, opioid blockade and sleep assessment methods as well as develop a solid foundation in biostatistical analyses. No research to date has examined the relationship between abnormal central pain processing, sleep disturbance, and mood with impaired endogenous opioid function. Consequently, the proposed research plan intends to investigate whether these risk factors share a neurobiological substrate that links them to important clinical pain outcomes following TKA, including persistent post-TKA pain, and increased opioid use. In particular, the proposed study will systematically evaluate the effectiveness of a direct pre- surgical test of endogenous opioid function via naloxone challenge in predicting post-operative pain and opioid use following TKA. Additional work will examine whether endogenous opioid function is associated with abnormal central pain processing, sleep disturbance, and pain related negative thinking on pain. Understanding the risk factors and underlying mechanisms whereby they exert their influence on outcomes following TKA, will have important implications for the selection of surgical patients, inform the management of post-operative pain, improve the health-related quality of life of individuals with chronic pain, and assist in the development of interventions designed to reduce the impact of the risk factors studied in this proposal. The candidate's long term goal is to refine biopsychosocial models of pain and facilitate the development or enhancement of therapeutic interventions for post-operative pain and to prevent chronicity. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) affects 20 million older Americans and the prevalence of knee OA is projected to dramatically increase as the U.S. population ages. Pain is the most common symptom associated with degenerative joint disease and is aggravated by abnormal functioning of central pain modulatory systems, sleep disturbance, and negative thinking. The proposed study will increase understanding of the mechanisms by which these factors impact pain related outcomes following total knee arthroplasty (TKA). Findings from this study will be used to alter modifiable risk factors associated with the development of chronic pain and to develop and refine psychosocial interventions for post-operative pain.